EP0055546B1 - Pentacyclic compounds, processes for their preparation and their use - Google Patents
Pentacyclic compounds, processes for their preparation and their use Download PDFInfo
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- EP0055546B1 EP0055546B1 EP81305861A EP81305861A EP0055546B1 EP 0055546 B1 EP0055546 B1 EP 0055546B1 EP 81305861 A EP81305861 A EP 81305861A EP 81305861 A EP81305861 A EP 81305861A EP 0055546 B1 EP0055546 B1 EP 0055546B1
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- Prior art keywords
- hydrogen
- alkyl
- compound
- formula
- phenyl
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- 0 CC(*)(CC(CN(*)C[C@@]1C2=C(*3)C=C*(*)C=C2)N1C1=C3C=C*(*)C=C1)O Chemical compound CC(*)(CC(CN(*)C[C@@]1C2=C(*3)C=C*(*)C=C2)N1C1=C3C=C*(*)C=C1)O 0.000 description 3
- ISGCVVPZXZUXAS-UHFFFAOYSA-N CN(CC1C2)CC(C3=CC=CCC3=Cc3ccc4)N1c3c4C2=O Chemical compound CN(CC1C2)CC(C3=CC=CCC3=Cc3ccc4)N1c3c4C2=O ISGCVVPZXZUXAS-UHFFFAOYSA-N 0.000 description 1
- HCVHYYVRTRQDTP-UHFFFAOYSA-N CN(CC1CC2)CC3N1c1c2cccc1Cc1c3cccc1 Chemical compound CN(CC1CC2)CC3N1c1c2cccc1Cc1c3cccc1 HCVHYYVRTRQDTP-UHFFFAOYSA-N 0.000 description 1
- YNZZUKYBMVNCKV-UHFFFAOYSA-N CN(CC1CCO)CC(c2c(C3)cccc2)N1c1c3cccc1 Chemical compound CN(CC1CCO)CC(c2c(C3)cccc2)N1c1c3cccc1 YNZZUKYBMVNCKV-UHFFFAOYSA-N 0.000 description 1
- KLDCZFNVHYDBEM-UHFFFAOYSA-N CN(CC1CCO)CC2N1c(cccc1)c1Oc1c2cccc1 Chemical compound CN(CC1CCO)CC2N1c(cccc1)c1Oc1c2cccc1 KLDCZFNVHYDBEM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/18—Dibenzazepines; Hydrogenated dibenzazepines
- C07D223/20—Dibenz [b, e] azepines; Hydrogenated dibenz [b, e] azepines
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/08—Seven-membered rings having the hetero atoms in positions 1 and 4
- C07D267/12—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems
- C07D267/16—Seven-membered rings having the hetero atoms in positions 1 and 4 condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D267/20—[b, f]-condensed
Definitions
- This invention relates to compounds having mood modifying, particularly anti-depressant and anxiolytic activity, to pharmaceutical compositions containing them and to processes for their preparation.
- the present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: wherein:
- R When X is NR, suitable values for R include hydrogen, methyl or ethyl, preferably methyl. Often X will be CH 2 . .
- Suitable values of Y and Z include hydrogen, methyl, ethyl; methoxy and ethoxy; fluoro, chloro and bromo; and CF 3 .
- both Y and Z will be hydrogen.
- Y when other than hydrogen is preferably in the 8-position, i.e. para to the piperazine nitrogen atom.
- Suitable values for R include hydrogen, methyl, ethyl, n- and iso-propyl; n, sec- and tert-butyl; phenethyl, benzyl or phenyl any of which phenyl moieties may be substituted by one or more of methyl, ethyl, n- and iso-propyl; methoxy, ethoxy, n- and iso-propoxy; fluoro, chloro, bromo or CF 3 .
- R 1 is hydrogen, methyl, phenyl or benzyl. Often R, will be hydrogen.
- Suitable values for R 2 include hydrogen, OH, methoxy, ethoxy, n- and iso-propoxy, benzyloxy, n-sec, and tert-butoxy; acetoxy, propionyloxy, n-, and iso- butyryloxy or NR 4 1 R 5 1 wherein R 4 1 and R 5 1 are independently selected from hydrogen, methyl, ethyl, n and iso-propyl; or n-, sec- and tert-butyl; R 4 is hydrogen and R 5 is OH or OCH 3 or R 4 and R 5 together form ⁇ (CH 2 ) 4 , ⁇ (CH 2 ) 5 ⁇ ⁇ (CH 2 ) 2 ⁇ (CH 2 ) 2 ⁇ or ⁇ (CH 2 ) 2 ⁇ NR 6 ⁇ (CH 2 ) 2
- R 3 include hydrogen, methyl, ethyl, n- and iso- propyl; and n-, sec- and tert-butyl.
- R 3 is methyl.
- R 1 Suitable and preferred values for R 1 are as described under formula (I).
- Suitable and preferred values for Y and Z are as defined in formula (I).
- R 1 1 will be hydrogen and R 2 1 will be hydroxy.
- One particularly preferred compound of this invention therefore is 4,5,5a,6,7,8,8a,13-0ctahydro-7-methyl-1,13c-diazabenzo[gh]pleiaden-4-ol.**
- a further sub-group of interest is of formula (V): wherein:
- a further sub-group of interest is of formula (Vi): wherein:
- R 1 and R 2 are as described under formula (I).
- Suitable examples of salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable inorganic and organic acids, such as hydrochloric hydrobromic, sulphuric. maleic- and succinic acids.
- the invention also provides a process for the preparation of a compound of formula (I) which process comprises the cyclisation of a compound of formula (VIII) or a salt thereof: wherein
- the cyclisation reaction is normally carried out under acid conditions using a dehydrating agent such as phosphorus pentoxide.
- a dehydrating agent such as phosphorus pentoxide.
- R 2 1 and R 2 2 together form an oxo group the reaction is normally carried out in methanesulphonic acid at room temperature.
- R 2 , and R 2 2 are both hydrogen, suitably excess phosphorus pentoxide is used, at elevated temperatures e.g. 100°C.
- the reduction step i) may be carried out with any of the usual carbonyl reducing agents under conditions which will be apparent to the skilled man.
- carbonyl reducing agents are metal hydride reducing agents such as lithium aluminium hydride in an organic solvent such as tetrahydrofuran or ether, or sodium borohydride in a lower alcohol at a temperature of 0 ⁇ 150°C.
- metal hydride reducing agents such as lithium aluminium hydride in an organic solvent such as tetrahydrofuran or ether, or sodium borohydride in a lower alcohol at a temperature of 0 ⁇ 150°C.
- a particularly favoured reducing agent is lithium aluminium hydride in ether.
- the reduction may be carried out by catalytic hydrogenation.
- the reaction with a Grignard reagent ii) may take place under conditions normally used in the art for this type of reaction, for example using R, 3 MgX wherein R, 3 is C 1 ⁇ 6 alkyl, phenyl or phenyl C 1 ⁇ 4 alkyl and X is a halogen usually chlorine, bromine or iodine in an inert solvent such as ether or tetrahydrofuran.
- R, 3 Li wherein R, 3 is as defined above, in an inert solvent.
- the compound H 2 NOR 7 is reacted with the compound of formula (I) [step (iii)] at a temperature between 0-150°C according to the reactivity of the compound H 2 NOR 7 employed.
- R 2 hydroxy groups may be converted to C 1 ⁇ 6 alkoxy or optionally substituted phenyl C 1 ⁇ 6 alkoxy groups by example, reaction with a compound R 2 2 L wherein R 2 2 is C 1 ⁇ 6 alkyl or phenyl C 1 ⁇ 6 alkyl and L is a good leaving group such as halogen or a tosylate residue, under basic conditions.
- the R 2 hydroxy group is converted to an alkoxide ion by the action of strong base and then reacted with R 2 L 1 wherein L 1 is a halogen, suitably bromine. More usually, the conversion may be achieved by heating with R 2 2 OH and an acid such as hydrochloric acid.
- R 2 hydroxy groups may be converted to C 1 ⁇ 7 acyloxy groups under acylation conditions which will be apparent to the skilled man.
- acylation is carried out with a C 1 ⁇ 7 carboxylic acid or a reactive derivative thereof in an inert solvent.
- the 'reactive derivative' will be the acid halide such as the acid chloride, in an inert solvent such as benzene or diethyl ether at 0-50°C.
- Other reactive derivatives of the C 1 ⁇ 7 carboxylic acid include anhydrides.
- the reaction may be carried out under basic conditions, for example, in pyridine as solvent to facilitate the reaction where necessary.
- R 2 hydroxy groups may be converted to hydrogen by reduction.
- One suitable method is to dehydrate the compound of formula (I) wherein R 2 is hydroxy under acid conditions and to subsequently catalytically hydrogenate the resulting olefinic double bond.
- Alkylation of NH 2 to NR 4 R s wherein one or both of R 4 and R 5 are C 1 ⁇ 6 alkyl, or NHR 4 to NR 4 R 5 wherein R 4 and R 5 are C 1 ⁇ 6 alkyl may be carried out in conventional manner, for example using an excess of an C 1 ⁇ 6 alkyl halide in a base such as K 2 CO 3 in a solvent such as acetone or DMF at a temperature suitably in the range 55°C to 120°C. It will be appreciated that when R 4 and R 5 are different alkyl groups or only one of R 4 and R 5 is an alkyl group unwanted alkylation of R 4 or R 5 hydrogens may be prevented by adjusting conditions accordingly.
- alkylate by acylation followed by reduction.
- formylation followed by reduction results in monomethylation.
- the reduction may be carried out under standard conditions, such as using lithium aluminium hydride in ether or tetrahydrofuran.
- R 1 is other than hydrogen and R 2 is NR 4 R 5 in the compound of formula (I)
- R 2 is NR 4 R 5 in the compound of formula (I)
- Conditions for this reaction are those normally used in the art for these types of reactions.
- the invention thus also provides a process for the preparation of a compound of formula (I) wherein R 1 and R 2 are other than an oxo group which process comprises the reaction of a compound of formula (IX): under steps i), ii) or iii) as hereinbefore defined.
- the route shown in Scheme 1 marked series 'A' involves a stereospecific cyclisation reaction so that the resulting compounds of the formulae (XI) and (VIII) are of one diastereoisomeric form only.
- The, route marked series 'B' involves a non-stereospecific cyclisation reaction and a mixture of diastereoisomers of compounds of formula (XI) is formed.
- the diastereoisomers of formula (XI) may be separated by conventional methods such as column chromatography before subsequent hydrolysis to the acid (VIII),
- Compound of formula (X) may be prepared as described in U.K. Patents 1,173,783 and 1,229,253 or U.S. Patents 3,534,041 and 3,701,778 or by analogous methods thereto.
- the present invention also provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier.
- composition of this invention will normally and preferably be adapted for oral administration although parenteral compositions are also envisaged as useful.
- compositions of this invention will most suitably be presented as unit dose compositions containing from 1 to 200 mg, more usually from 5 to 100 mg, for example 10 to 50 mg such as 12.5, 15, 20, 25 or 30 mg. Such compositions will normally be taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg.
- Preferred unit dosage forms include tablets, capsules and their equivalents.
- compositions of this invention may be formulated by conventional methods of blending, filling, compressing and the like.
- Suitable carriers for use in this invention include diluents, binders, disintegrants, colouring agents, flavouring agents, preservatives and the like. These agents may be utilized in conventional manner, for example in a manner similar to that already used for other mood modifying agents such as clinically used anti-depressant and anxiolytic agents.
- 6-methylaminomethyl-5,6-dihydromorphanthridine (20 g, 0.084 mol) was dissolved in dry dimethylformamide (1 50 mI).
- potassium carbonate (11.6 g, 0.084 mol) was added and to the resulting mixture stirred at room temperature, methyl-4-bromocrotonate (85%, 17.6 g, 0.084 mol) was added dropwise.
- the reaction mixture was stirred at room temperature for 4 hours (the reaction followed by t.l.c. on silica gel eluted with diethyl ether). When t.l.c. indicated that the reaction was complete, the solvent was removed and ether (100 ml)/water (200 ml) added to the residue.
- Methyl-4-(methylaminomethyl-5,6-dihydro-6-morphanthridinyl)but-2-enoate (1.5 g) (description 1 a) was dissolved in methanesulphonic acid (20 ml.) and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was poured onto ice/water basified with sodium hydroxide and extracted with ethyl acetate (3 x 25 mI). Removal of the solvent in vacuo gave a brown oil which was purified by column chromatography on silica gel eluted with ether.
- the thus formed ketone was converted to the maleate salt which after recrystallisation from methanol/ether had a melting point of 176-179°C.
- the ketone (13 g, 0.042 m) was dissolved in dry ether (150 ml) and lithium aluminium hydride (0.8 g, 0.02 m) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes until t.l.c. indicated that no ketone remained.
- the major product (3) was isolated in 85% yield as a white solid mp 160 ⁇ 161°C after recrystallisation from a mixture of ethyl acetate and ether.
- the alcohol was converted to the maleate salt which after recrystallization from methanol/ether had a melting point of 191-193 0 C.
- the catalyst was filtered off and the solvent removed in vacuo to give a brown solid.
- Phenylmagnesium bromide was prepared from bromobenzene (0.78 g, 0.005 mol) and magnesium (0.12 g, 0.005 mol) using dry THF as solvent. To this mixture was added the ketone (0.5 g, 0.0016 mol) in dry THF. The reaction mixture was stirred at room temperature for 2 hours before ammonium chloride was added and the product extracted into ethyl acetate. Column chromatography on silica gel eluted with ether gave the desired compound which was converted to the maleate salt and recrystallised from acetone/ether in 33% yield with melting point 220-202°C. Mass spectrum m/e 382.
- the minor product was obtained in 19% yield recrystallised from ethyl acetate/60-80°C petroleum ether and had melting point 136-138°C.
- the product was obtained in 28% yield after column chromatography on silica gel eluted with ether and had melting point 197-199°C.
- the major product (13) was converted to the maleate salt and recrystallised from acetone/ether in 32% yield and had melting point 168-171 °C.
- Example 2A The alcohol of Example 2A, Compound 3 (0.5 g) was dissolved in pyridine (20 ml) and acetic anhydride (10 ml) added dropwise. The mixture was stirred at room temperature overnight, basified and extracted with ethyl acetate. The organic extract was washed well with water, dried (MgSO d ), and the solvent removed to give a brown oil. Column chromatography on silica gel eluted with ether gave the title compound as white crystals in 37% yield.
- the acetoxy analogue was converted to the maleate salt which after recrystallisation from acetone/ether had melting point of 161-164°C.
- Example 1A In a similar manner to Example 1A the title compound was obtained in 39% yield, converted to the maleate salt and recrystallised from acetone/ether, mp 187-188°C.
- Example 3B In a similar manner to Example 3B the alcohol of Description 5 was heated in PPA at 100°C for 2 hours. The product was purified on silica gel column eluted with ether and obtained in 26% yield. It was converted to.the maleate salt and recrystallised from acetone/ether as white crystals, mp 173-176°C.
- Example 1 A The title compound was prepared in a similar manner to that outlined in Example 1 A.
- the ketone was obtained in 44% yield, converted to maleate salt and recrystallised from acetone/ether, mp 179-180°C.
- the ketone is prepared in an analogous manner to that outlined in Example 1 A.
- Compounds of the invention inhibit the behavoural symptoms induced by 5-methoxy-N,N-dimethyl tryptamine, a central 5-hydroxytryptamine agonist, and are central 5HT antagonists. As such they would be expected to possess anti-depressant, (Ogren, S 0, Furce, K, Agnati, L F, Gustofoson J A, Jonsson, G, and Holan A C, 1979, J. Neural Erous, 46, 85-103) and/or anxiolytic (Stein, L, Wline, D, and Bellugi, J D, 1975, in Advance-Biochemical Psychopharmocology, ed Corta, E, and Greengord, P, Vol. 14, 29-44, Rouen Press, NY) activity.
- anti-depressant Ogren, S 0, Furce, K, Agnati, L F, Gustofoson J A, Jonsson, G, and Holan A C, 1979, J. Neural Erous, 46, 85-103
- mice (d CD-' Charles Rine) are pretreated with the compounds 10 animals/group under investigation and 1 h later one group is injected with 10 mg/kg ip 5-methoxy-N,N-dimethyltryptamine (Sigma).
- the symptoms of forepaw tapping movements, head jerks and splayed limbs are scored: 1, present; 0 absent, giving a maximum score of 3/mouse or 30/group. Results are expressed as the percentage inhibition compared to the group treated with 5-methoxy-N,N-dimethyl tryptamine alone.
- the dose of compound inhibiting the symptoms by 50% is determined graphically.
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Description
- This invention relates to compounds having mood modifying, particularly anti-depressant and anxiolytic activity, to pharmaceutical compositions containing them and to processes for their preparation.
-
- R, and R3 represent a hydrogen or halogen atom, a hydroxy, lower acyloxy, alkyl or alkoxy group, or a trifluormethyl group;
- R2 represents hydrogen, a lower alkyl or aralkyl group, an aminoethyl or aminopropyl group N-substituted by one or more lower alkyl groups, or a lower alkyl group forming a substituent of an N-containing heterocyclic ring, the said ring being directly bonded to the nitrogen atom or the piperazine ring, and
- P represents a single bond, or a methylene, ethylene or -CH=CH- group.
-
- R1 and R2 represent hydrogen, halogen, hydroxyl, acyloxy, alkyloxy or alkyl having 1-6 carbon atoms, or trifluoromethyl groups;
- R2 represents hydrogen, an alkyl group having 1-6 carbon atoms, an aralkyl group with 7-12 carbon atoms, an aminoethyl or aminopropyl group, which, if desired, can be substituted in the N-position by an alkyl group with 1-6 carbon atoms, or an alkyl group having 1-6 carbon atoms and a nitrogen-containing heterocyclic ring; and
- X represents oxygen, sulphur, or
- We have now discovered a structurally distinct class of compounds which also have mood- modifying activity.
-
- X is CH2, 0, S or NR wherein R is hydrogen or C1―4 alkyl;
- Y and Z are independently selected from hydrogen, C1―4 alkyl, C1―4 alkoxy, halogen or CF3;
- R1 is hydrogen, C1―6 alkyl, phenyl or phenyl-C1―4 alkyl any of which phenyl moieties may be substituted by one or more of C1―6alkyl, C1―6 alkoxy, halogen or CF3;
- - R2 is hydrogen, OH, C1―6 alkoxy, phenyl-C1―4 alkoxy, C1―7 acyloxy or NR4R5 wherein R4 and R5 are independently selected from hydrogen or C1―6 alkyl; R4 is hydrogen and R5 is OH or C1―4 alkoxy; or R4 and R5 together form C3―6 polymethylene optionally interrupted by 0 or NR6 where R6 is hydrogen or C1―4 alkyl; or together with R1 forms an oxo group or =NOR7 wherein R7 is hydrogen or C1―6 alkyl; and
- R3 is hydrogen or C1―6 alkyl.
- When X is NR, suitable values for R include hydrogen, methyl or ethyl, preferably methyl. Often X will be CH2..
- Suitable values of Y and Z include hydrogen, methyl, ethyl; methoxy and ethoxy; fluoro, chloro and bromo; and CF3. Favourably both Y and Z will be hydrogen. Y when other than hydrogen is preferably in the 8-position, i.e. para to the piperazine nitrogen atom. Suitable values for R, include hydrogen, methyl, ethyl, n- and iso-propyl; n, sec- and tert-butyl; phenethyl, benzyl or phenyl any of which phenyl moieties may be substituted by one or more of methyl, ethyl, n- and iso-propyl; methoxy, ethoxy, n- and iso-propoxy; fluoro, chloro, bromo or CF3. Favourably R1 is hydrogen, methyl, phenyl or benzyl. Often R, will be hydrogen.
- Suitable values for R2 include hydrogen, OH, methoxy, ethoxy, n- and iso-propoxy, benzyloxy, n-sec, and tert-butoxy; acetoxy, propionyloxy, n-, and iso- butyryloxy or NR4 1R5 1 wherein R4 1 and R5 1are independently selected from hydrogen, methyl, ethyl, n and iso-propyl; or n-, sec- and tert-butyl; R4 is hydrogen and R5 is OH or OCH3 or R4 and R5 together form ―(CH2)4 , ―(CH2)5― ―(CH2)2―(CH2)2― or ―(CH2)2―NR6―(CH2)2
- Favourably R3 include hydrogen, methyl, ethyl, n- and iso- propyl; and n-, sec- and tert-butyl. Preferably R3 is methyl.
- There is a group of compounds within formula (I) wherein Y and Z are both hydrogen, R1 and R2 are as defined in formula (I) except that they do not together form oxo or =NOR7 and X and R3 are as defined in formula (I).
-
- Y and Z, R1 and R2 are as defined in formula (I).
- Suitable and preferred values for R1 are as described under formula (I).
-
- R1 1 is hydrogen, methyl, phenyl or benzyl;
- R2 1 is hydroxy, methoxy, acetoxy or benzyloxy; and
- Y and Z are as defined in formula (I).
- Suitable and preferred values for Y and Z are as defined in formula (I).
- Preferably R1 1 will be hydrogen and R2 1 will be hydroxy.
- One particularly preferred compound of this invention therefore is 4,5,5a,6,7,8,8a,13-0ctahydro-7-methyl-1,13c-diazabenzo[gh]pleiaden-4-ol.**
- Another suitable sub-group of compounds within formula (II) is of formula (IV):
- ** (i.e. the compound of formula (III) above wherein R1 1 is H and R1 2 is hydroxy).
- R1 1 is hydrogen, methyl, phenyl or benzyl;
- Often R1 1 will be hydrogen.
-
- Q is oxygen or NOR7 wherein R7 is as defined in formula (I).
-
- X' is 0 or S and R1 and R2 are as defined in formula (I).
-
- X" is NR as defined in formula (I) and R1 and R2 are as defined in formula (I).
- Suitable and preferred values of R1 and R2 are as described under formula (I).
- Compounds of the formula (I) have more than one asymmetric centre and are capable of existing in a number of stereoisomeric forms. The invention extends to each of these forms and to mixtures thereof (including racemates). The isomers may be separated from one another using conventional techniques, such as chromatography. These compounds hereinafter referred to as the 'A' series isomers are generally preferred.
- Suitable examples of salts of the compounds of formula (I) include acid addition salts with pharmaceutically acceptable inorganic and organic acids, such as hydrochloric hydrobromic, sulphuric. maleic- and succinic acids.
-
- R2, is hydrogen, C1―6 alkyl, phenyl or phenyl-C1―4 alkyl any of which phenyl moieties may be substituted by one or more of C1―6 alkyl, C1―6 alkoxy, halogen or CF3; and
- R2 2 is hydrogen, or R2 1 and R2 2 together form an oxo group and X, Y, Z and R3 are as defined in formula (I) with a dehydrating agent and thereafter if desired or necessary reacting a resulting compound of formula (I) wherein R1 and R2 form an oxo group with:
- i) a carbonyl reducing agent to form a compound of formula (I) wherein R1 is hydrogen and R2 is hydroxy;
- ii) a C1―6 alkyl, phenyl or phenyl C1―4 alkyl Grignard reagent or equivalent metallic complex reagent to form a compound wherein R, is other than hydrogen and R2 is hydroxy; or
- iii) H2NOR7, to form a compound wherein R, and R2 together form =NOR7 group; and thereafter if desired or necessary converting R2 when hydroxy to hydrogen, C1―6 alkoxy, phenyl C1―4 alkoxy or C1―7 acyloxy and/or alkylating R2 when NHR4 or NH2 to NR4R5 or interconverting R2 or forming a pharmaceutically acceptable salt.
- The cyclisation reaction is normally carried out under acid conditions using a dehydrating agent such as phosphorus pentoxide. When R2 1 and R2 2 together form an oxo group, the reaction is normally carried out in methanesulphonic acid at room temperature. When R2, and R2 2 are both hydrogen, suitably excess phosphorus pentoxide is used, at elevated temperatures e.g. 100°C.
- The reduction step i) may be carried out with any of the usual carbonyl reducing agents under conditions which will be apparent to the skilled man. Suitable examples of carbonyl reducing agents are metal hydride reducing agents such as lithium aluminium hydride in an organic solvent such as tetrahydrofuran or ether, or sodium borohydride in a lower alcohol at a temperature of 0―150°C. A particularly favoured reducing agent is lithium aluminium hydride in ether. Alternatively, the reduction may be carried out by catalytic hydrogenation.
- The reaction with a Grignard reagent ii) may take place under conditions normally used in the art for this type of reaction, for example using R,3 MgX wherein R,3 is C1―6 alkyl, phenyl or phenyl C1―4 alkyl and X is a halogen usually chlorine, bromine or iodine in an inert solvent such as ether or tetrahydrofuran. Other equivalent metallic complex reagents include R,3Li wherein R,3 is as defined above, in an inert solvent.
- The compound H2NOR7 is reacted with the compound of formula (I) [step (iii)] at a temperature between 0-150°C according to the reactivity of the compound H2NOR7 employed.
- R2 hydroxy groups may be converted to C1―6 alkoxy or optionally substituted phenyl C1―6 alkoxy groups by example, reaction with a compound R2 2 L wherein R2 2 is C1―6 alkyl or phenyl C1―6 alkyl and L is a good leaving group such as halogen or a tosylate residue, under basic conditions. Alternatively, the R2 hydroxy group is converted to an alkoxide ion by the action of strong base and then reacted with R2L1 wherein L1 is a halogen, suitably bromine. More usually, the conversion may be achieved by heating with R2 2 OH and an acid such as hydrochloric acid.
- R2 hydroxy groups may be converted to C1―7 acyloxy groups under acylation conditions which will be apparent to the skilled man. Suitably acylation is carried out with a C1―7 carboxylic acid or a reactive derivative thereof in an inert solvent. Often the 'reactive derivative' will be the acid halide such as the acid chloride, in an inert solvent such as benzene or diethyl ether at 0-50°C. Other reactive derivatives of the C1―7 carboxylic acid include anhydrides. Optionally the reaction may be carried out under basic conditions, for example, in pyridine as solvent to facilitate the reaction where necessary.
- R2 hydroxy groups may be converted to hydrogen by reduction. One suitable method is to dehydrate the compound of formula (I) wherein R2 is hydroxy under acid conditions and to subsequently catalytically hydrogenate the resulting olefinic double bond.
- Alkylation of NH2 to NR4Rs wherein one or both of R4 and R5 are C1―6 alkyl, or NHR4 to NR4R5 wherein R4 and R5 are C1―6 alkyl may be carried out in conventional manner, for example using an excess of an C1―6 alkyl halide in a base such as K2CO3 in a solvent such as acetone or DMF at a temperature suitably in the range 55°C to 120°C. It will be appreciated that when R4 and R5 are different alkyl groups or only one of R4 and R5 is an alkyl group unwanted alkylation of R4 or R5 hydrogens may be prevented by adjusting conditions accordingly. It is normally preferable, however, to alkylate by acylation followed by reduction. For example, formylation followed by reduction results in monomethylation. The reduction may be carried out under standard conditions, such as using lithium aluminium hydride in ether or tetrahydrofuran.
- Other methods of interconverting Rz groups will be apparent to the skilled man. For example, when R1 is other than hydrogen and R2 is NR4R5 in the compound of formula (I), it is desirable to prepare the corresponding compound wherein R2 is hydroxy and convert this compound to a compound wherein R2 is replaced by a good leaving group such as halide or an activated ester group, for example a tosylate residue and react this with a compound HNR4R5. Conditions for this reaction are those normally used in the art for these types of reactions.
- The compounds of formula (VIII) are novel and thus form an aspect of the present invention as intermediates.
-
-
- The route shown in Scheme 1 marked series 'A' involves a stereospecific cyclisation reaction so that the resulting compounds of the formulae (XI) and (VIII) are of one diastereoisomeric form only. The, route marked series 'B' involves a non-stereospecific cyclisation reaction and a mixture of diastereoisomers of compounds of formula (XI) is formed. The diastereoisomers of formula (XI) may be separated by conventional methods such as column chromatography before subsequent hydrolysis to the acid (VIII),
- Compound of formula (X) may be prepared as described in U.K. Patents 1,173,783 and 1,229,253 or U.S. Patents 3,534,041 and 3,701,778 or by analogous methods thereto.
- The present invention also provides a pharmaceutical composition which comprises a compound of this invention and a pharmaceutically acceptable carrier.
- The composition of this invention will normally and preferably be adapted for oral administration although parenteral compositions are also envisaged as useful.
- The composition of this invention will most suitably be presented as unit dose compositions containing from 1 to 200 mg, more usually from 5 to 100 mg, for example 10 to 50 mg such as 12.5, 15, 20, 25 or 30 mg. Such compositions will normally be taken from 1 to 6 times daily, for example 2, 3 or 4 times daily so that the total amount of active agent administered is within the range 5 to 400 mg.
- Preferred unit dosage forms include tablets, capsules and their equivalents.
- The compositions of this invention may be formulated by conventional methods of blending, filling, compressing and the like.
- Suitable carriers for use in this invention include diluents, binders, disintegrants, colouring agents, flavouring agents, preservatives and the like. These agents may be utilized in conventional manner, for example in a manner similar to that already used for other mood modifying agents such as clinically used anti-depressant and anxiolytic agents.
- The following Examples illustrate the invention.
- The following Descriptions illustrate the preparation of intermediates.
-
- 6-methylaminomethyl-5,6-dihydromorphanthridine (20 g, 0.084 mol) was dissolved in dry dimethylformamide (1 50 mI). To this solution, potassium carbonate (11.6 g, 0.084 mol) was added and to the resulting mixture stirred at room temperature, methyl-4-bromocrotonate (85%, 17.6 g, 0.084 mol) was added dropwise. The reaction mixture was stirred at room temperature for 4 hours (the reaction followed by t.l.c. on silica gel eluted with diethyl ether). When t.l.c. indicated that the reaction was complete, the solvent was removed and ether (100 ml)/water (200 ml) added to the residue. The organic layer was separated and the aqueous further extracted with 2 x 50 ml portions of ether. The organic extracts were combined, dried (MgS04) and the solvent removed in vacuo to give a brown oil. Purification of the product was achieved by filtration through a short column of silica gel eluted with ether. The title product was obtained as a brown oil in 65% yield.
-
- The compound prepared in (a) was heated to 1 50°C with stirring under nitrogen, then kept at this temperature for a further 2-3 hours (the reaction was followed by intra-red spectroscopy until the N-H band of the starting material became insignificant). The product was then dissolved in ether and filtered through a short column of silica gel. Removal of the solvent gave the title compound in 65% yield as a brown oil.
- A sample was converted to the hydrochloride salt and recrystallised from methanol/ether to give white crystals m.p. 259-262°C.
-
- The ester prepared in (b) (10 g) was heated under reflux in 5N hydrochloric acid (150 ml) for 2 hours. On cooling, the hydrochloride salt of the title acid precipitated as a white solid. After filtration, washing with water and drying in a vacuum oven, the yield of the title compound was 90%. Recrystallisation from acetone gave the title compound as an off-white solid (m.p. 268-270°C).
-
- Methyl-4-(methylaminomethyl-5,6-dihydro-6-morphanthridinyl)but-2-enoate (1.5 g) (description 1 a) was dissolved in methanesulphonic acid (20 ml.) and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was poured onto ice/water basified with sodium hydroxide and extracted with ethyl acetate (3 x 25 mI). Removal of the solvent in vacuo gave a brown oil which was purified by column chromatography on silica gel eluted with ether.
- 0.25 g (35%) of ester diastereomer A was isolated
- 0.78 g (52%) of ester diastereomer B was isolated
- Ester B was converted to the hydrochloride salt and recrystallized from methanol/ether to give white crystals m.p. 231-234°C.
-
-
- The ester prepared in (a) (5 g) was heated under reflux in 10% sodium hydroxide for 2 hours. The reaction mixture was then acidified with 5N hydrochlorid acid. As the solution cooled the hydrochloride salt of the acid precipitated as a white solid. The solid was filtered, washed with water and dried in a vacuum oven. After drying the yield was 85%, mp 295-299°C.
-
- The ester (5 g) was dissolved in dry diethyl ether (10 ml) and excess lithium aluminium hydride (0.6 g) was added in portions to the stirred mixture. The reaction mixture was stirred at room temperature for 30 mins until t.l.c. (silica gel/ether) indicated no ester remained.
- Water (0.6 ml), 15% sodium hydroxide (0.6 ml) and water (1.8 ml) were added and the mixture filtered. Removal of the solvent gave the alcohol in 45% yield as a white solid.
-
-
-
-
-
- Column chromatography on silica gel eluted with ethyl acetate gave the required product in 63% yield.
-
-
- The acid prepared in (c) (1.2 g, 0.0033 mol) was dissolved in methanesulphonic acid (12 g) and phosphorus pentoxide (2.4 g, 0.016 mol) was added in portions, with cooling. The reaction mixture was stirred at room temperature for 3 days then poured onto ice/water, basified with sodium hydroxide and extracted with ethyl acetate (3 x 25 mI). The organic extracts were combined, washed with water (2 x 20 ml) dried (MgSO4.H2O) and the solvent removed in vacuo and the crude ketone was obtained as an off white foam. Column chromatography on silica gel eluted with ether together with increasing proportion of ethyl acetate, gave the title compound as a white foam in 45% yield. This was converted to the hydrochloride salt and recrystallised from ethanol, mp 289-291 °C.
-
- In a similar manner to .Example 1A the title compound was prepared from the compound o1 description 2b in 53% yield.
-
-
- The ketone (13 g, 0.042 m) was dissolved in dry ether (150 ml) and lithium aluminium hydride (0.8 g, 0.02 m) was added in portions. The reaction mixture was stirred at room temperature for 30 minutes until t.l.c. indicated that no ketone remained.
- Water (0.8 ml), 15% sodium hydroxide (0.8 ml) and water (2.4 ml) were added and the mixture filtered. (The collected inorganic solid was washed several times with ethyl acetate). The filtrate was concentrated in vacuo and the product purified by silica gel column chromatography using ethyl acetate with increasing proportions of ethanol as eluant. Both possible epimeric alcohols (3) and (4) obtained (ratio 90%:10%). Mass spectrum m/e 306, fragmentation patterns identical.
-
-
-
- In a similar manner to example 2A the title compound was prepared from compound 2.
- The alcohol was converted to the maleate salt which after recrystallization from methanol/ether had a melting point of 191-1930C.
-
- The alcohol of example 2A (8 g, 0.026 mol) was dissolved in benzene (100 ml) and toluene-4-sulphonic acid (9.9 g, 0.052 mol) added. The reaction mixture was refluxed using a Dean and Stark trap to remove water. Reflux was continued until t.l.c. (silica gel/ether) indicated no alcohol remained. The organic layer was washed twice with saturated sodium bicarbonate solution (2 x 25 ml), dried (MgS04) and the solvent removed in vacuo to give a brown oil in 99% yield. This product was hydrogenated at atmospheric pressure in ethyl acetate using 10% palladium on charcoal as catalyst until hydrogen uptake had ceased.
- The catalyst was filtered off and the solvent removed in vacuo to give a brown solid.
- Column chromatography on silica gel eluted with ether together with increasing proportion of ethyl acetate gave the title compound as a white solid in 23% yield. This was converted to the maleate salt and recrystallized from methanol/ether to give white crystals, mp 189-191 °C.
Mass Spectrum m/e 290. -
- Alcohol (0.4 g) was heated in excess polyphosphoric acid at 100°C for 2 hours. The reaction nixture was poured onto ice/water and basified with 40% sodium hydroxide. The pentacyclic product was extracted into ethyl acetate.
- Column chromatography on silica gel eluted with ethyl acetate gave the required product in 76% yield as a brown oil.
-
-
- To a mixture of ketone (1 g, 0.0032 mol), hydroxylamine hydrochloride (0.35 g, 0.005 mol), ethanol (2 ml) and water (0.5 ml) was added sodium hydroxide (0.65 g, 0.016 mol) in portions. The resulting mixture was refluxed for 10 mins and then extracted with ethyl acetate. The crude product, purified by column chromatography on silica gel eluted with ether, was obtained as a white solid in 58% yield mp 216-219°C.
-
-
- Phenylmagnesium bromide was prepared from bromobenzene (0.78 g, 0.005 mol) and magnesium (0.12 g, 0.005 mol) using dry THF as solvent. To this mixture was added the ketone (0.5 g, 0.0016 mol) in dry THF. The reaction mixture was stirred at room temperature for 2 hours before ammonium chloride was added and the product extracted into ethyl acetate. Column chromatography on silica gel eluted with ether gave the desired compound which was converted to the maleate salt and recrystallised from acetone/ether in 33% yield with melting point 220-202°C.
Mass spectrum m/e 382. -
- Alcohol (2 g, compound 3) was dissolved in dichloromethane (40 ml) and triethylamine (1 ml) added. The solvent was cooled to -10°C using dry ice/acetone bath and methanesulphonyl chloride (0.5 ml) was added keeping the reaction mixture at -10°C.
- The mixture was allowed to rise to 0°C over approx. 30 mins then excess dimethylamine solution in 1 MS was added. The solution was stirred at 0°C for 15 mins, then allowed to stir at room temperature overnight.
- Column chromatography on silica gel eluted with ether gave the two epimeric amines (ratio 75%:25%). Mass spectrum fragmentation patterns identical.
-
-
-
- In a similar manner the title compound was prepared from compound 3 of Example 2A.
-
-
- A mixture of the two 'A' series alcohols (compounds 3 and 4) was treated with a methanol/dilute hydrochloric acid mixture at room temperature until t.l.c. (silica gel/ether) indicated no starting alcohol remained. The reaction mixture was evaporated to dryness, basified and extracted with ether. Column chromatography on silica gel eluted with ether gave the two possible epimeric methoxy derivatives (ratio 2:1). Both had mass spectrum m/e 320 with identical fragmentation patterns.
-
-
- The alcohol of Example 2A, Compound 3 (0.5 g) was dissolved in pyridine (20 ml) and acetic anhydride (10 ml) added dropwise. The mixture was stirred at room temperature overnight, basified and extracted with ethyl acetate. The organic extract was washed well with water, dried (MgSOd), and the solvent removed to give a brown oil. Column chromatography on silica gel eluted with ether gave the title compound as white crystals in 37% yield.
-
-
-
-
-
-
-
- In a similar manner to Example 3B the alcohol of Description 5 was heated in PPA at 100°C for 2 hours. The product was purified on silica gel column eluted with ether and obtained in 26% yield. It was converted to.the maleate salt and recrystallised from acetone/ether as white crystals, mp 173-176°C.
-
-
-
- The ketone is prepared in an analogous manner to that outlined in Example 1 A.
- Reduction of the ketone in an analogous manner to that described in Example 2A gives the corresponding alcohol (Compound 22).
- Compounds of the invention inhibit the behavoural symptoms induced by 5-methoxy-N,N-dimethyl tryptamine, a central 5-hydroxytryptamine agonist, and are central 5HT antagonists. As such they would be expected to possess anti-depressant, (Ogren, S 0, Furce, K, Agnati, L F, Gustofoson J A, Jonsson, G, and Holan A C, 1979, J. Neural Erous, 46, 85-103) and/or anxiolytic (Stein, L, Wline, D, and Bellugi, J D, 1975, in Advance-Biochemical Psychopharmocology, ed Corta, E, and Greengord, P, Vol. 14, 29-44, Rouen Press, NY) activity.
- Mice (d CD-' Charles Rine) are pretreated with the compounds 10 animals/group under investigation and 1 h later one group is injected with 10 mg/kg ip 5-methoxy-N,N-dimethyltryptamine (Sigma). The symptoms of forepaw tapping movements, head jerks and splayed limbs are scored: 1, present; 0 absent, giving a maximum score of 3/mouse or 30/group. Results are expressed as the percentage inhibition compared to the group treated with 5-methoxy-N,N-dimethyl tryptamine alone. The dose of compound inhibiting the symptoms by 50% is determined graphically.
- The results are shown in Table 1.
-
Claims (10)
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US (1) | US4442098A (en) |
EP (1) | EP0055546B1 (en) |
JP (1) | JPS57134483A (en) |
AU (1) | AU551160B2 (en) |
CA (1) | CA1167439A (en) |
DE (1) | DE3165289D1 (en) |
ES (1) | ES8401071A1 (en) |
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GR (1) | GR76380B (en) |
IE (1) | IE52235B1 (en) |
NZ (1) | NZ199291A (en) |
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DE3368634D1 (en) * | 1982-03-05 | 1987-02-05 | Beecham Group Plc | Pentacyclic compounds |
EP0090552A3 (en) * | 1982-03-27 | 1984-04-25 | Beecham Group Plc | Pentacyclic compounds |
JP2008509925A (en) * | 2004-08-13 | 2008-04-03 | オメロス コーポレイション | Novel serotonin receptor ligands and their use |
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NL154511B (en) * | 1967-07-07 | 1977-09-15 | Organon Nv | PROCESS FOR PREPARING PIPERAZINE DERIVATIVES, PROCESS FOR PREPARING A PHARMACEUTICAL PREPARATION CONTAINING SUCH A COMPOUND AND MOLDS PREPARED ACCORDING TO THIS PROCEDURE. |
-
1981
- 1981-12-14 EP EP81305861A patent/EP0055546B1/en not_active Expired
- 1981-12-14 GB GB8137604A patent/GB2091247B/en not_active Expired
- 1981-12-14 DE DE8181305861T patent/DE3165289D1/en not_active Expired
- 1981-12-16 NZ NZ199291A patent/NZ199291A/en unknown
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- 1981-12-30 CA CA000393370A patent/CA1167439A/en not_active Expired
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- 1981-12-30 JP JP56215973A patent/JPS57134483A/en active Pending
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DE3165289D1 (en) | 1984-09-06 |
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CA1167439A (en) | 1984-05-15 |
ES508465A0 (en) | 1983-11-16 |
US4442098A (en) | 1984-04-10 |
IE52235B1 (en) | 1987-08-19 |
AU551160B2 (en) | 1986-04-17 |
PT74210B (en) | 1983-05-30 |
ES8401071A1 (en) | 1983-11-16 |
GB2091247A (en) | 1982-07-28 |
EP0055546A1 (en) | 1982-07-07 |
GR76380B (en) | 1984-08-06 |
AU7913181A (en) | 1982-07-08 |
PT74210A (en) | 1982-01-01 |
GB2091247B (en) | 1984-07-18 |
IE813084L (en) | 1982-06-30 |
NZ199291A (en) | 1986-01-24 |
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